EP0344235B1 - Prostaglandin-derivate zur behandlung von glaucoma oder augenüberdruck - Google Patents

Prostaglandin-derivate zur behandlung von glaucoma oder augenüberdruck Download PDF

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Publication number
EP0344235B1
EP0344235B1 EP88908778A EP88908778A EP0344235B1 EP 0344235 B1 EP0344235 B1 EP 0344235B1 EP 88908778 A EP88908778 A EP 88908778A EP 88908778 A EP88908778 A EP 88908778A EP 0344235 B1 EP0344235 B1 EP 0344235B1
Authority
EP
European Patent Office
Prior art keywords
glaucoma
ocular hypertension
epi
pgf 2alpha
2alpha
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP88908778A
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English (en)
French (fr)
Other versions
EP0344235A1 (de
Inventor
Johan W. Stjernschantz
Bahram Resul
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Health AB
Original Assignee
Kabi Pharmacia AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kabi Pharmacia AB filed Critical Kabi Pharmacia AB
Priority to AT88908778T priority Critical patent/ATE78031T1/de
Publication of EP0344235A1 publication Critical patent/EP0344235A1/de
Application granted granted Critical
Publication of EP0344235B1 publication Critical patent/EP0344235B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof

Definitions

  • the invention is concerned with the use of derivatives of a specific diastereomer of prostaglandin F 2alpha , viz. 11 epi, for the treatment of glaucoma or ocular hypertension.
  • the invention furthermore also relates to ophthalmological compositions containing an active amount of these prostaglandin derivatives.
  • Glaucoma is an ocular disorder characterized by elevated intraocular pressure, excavation of the optic nerve head and gradual loss of the vision field.
  • An abnormally high intraocular pressure will have a generally detrimental effect on the eye; and there are clear indications that this is probably the main factor causing degenerative changes of the retina in glaucoma patients.
  • the pathophysiological mechanism underlying open-angle glaucoma is still unknown. If not treated successfully the disease will usually proceed to blindness sooner or later, its course towards that stage being characterized by a slow but progressive loss of vision.
  • This uveoscleral path has been described by e.g. Bill (1975).
  • the pressure gradient along this path is very insignificant as compared to the gradient in the first mentioned case over the interior wall of Schlemm's canal and adjacent tissue.
  • the flow-limiting step along the uveoscleral path is believed to reside in the flow from the anterior chamber into the suprachoroidal space.
  • IOP P e + (F t - F u ) x R
  • P e and R have the same meanings as above
  • F t represents the total outflow: of aqueous humor
  • F u represents that portion thereof which goes via the uveoscleral path.
  • the IOP will normally be within the range of from 12 to 22 mm Hg. At higher values, e.g. exceeding 22 mm Hg, there is a risk that the eye may be affected.
  • the so-called low-tension glaucoma lesions will occur at intraocular pressure levels which are generally regarded as physiological. Possibly this may be due to an increased pressure sensitivity of the eye of such an individual.
  • the opposite type of phenomenon is known, i.e. some individuals may have in abnormally high intraocular pressure without any noticeable distinct defects in their vision field or optic nerve head. Such conditions are usually named "ocular hypertension".
  • Glaucoma treatments may be given by means of drugs, laser or surgery.
  • the purpose is to achieve a reduction of either the flow (F) or the resistance (R), which will result in a lower IOP according to formula (1) above; or alternatively, the purpose may be to increase the flow via the uveoscleral path - which too will be a means of lowering the pressure as can be seen from formula (2).
  • Cholinergic agonists like for instance pilocarpine reduce the intraocular pressure mainly by increasing the outflow through Schlemm's canal.
  • prostaglandins and derivatives thereof are described in for example US 4599353 and EP 87103714.9.
  • prostaglandins and derivatives as suitable as drugs for treating glaucoma or ocular hypertension, a limiting factor is their property of causing superficial irritation and vasodilatation in the conjunctiva. It is probable moreover that prostaglandins have an irritant effect on the sensory nerves of the cornea. Thus local side effects will arise in the eye already when the amounts of prostaglandin administered are quite small - that is, already when the doses are lower than those that would be desirable for achieving maximum pressure reduction. It has thus been found for instance that for this reason. It is clinically impossible to use PGF2 alpha -1-isopropyl ester in the amount that would give maximum: pressure reduction.
  • Prostaglandins being naturally occurring autacoids are very potent pharmacologically any affect both sensory nerves and smooth muscle of the blood vessels. Since the effects caused by administrations of PGF 2alpha and its esters to the eye comprise in addition to pressure reduction also irritation and hyperemia (increased blood flow) the doses currently practicable in clinical tests are necessarily very low.
  • the irritation experienced when PGF 2alpha or its esters are applied consists mainly in a feeling of grittiness or of having a foreign body in one's eye, this beinG usually. accompanied by increased lacrimation.
  • the 11 epi PGF 2alpha -1-isopropyl ester which as far as we know has not been described heretofore will give rise to hyperemia in the conjunctiva to about the same extent as the PGF 2alpha -1-isopropyl ester, but this will not involve any hazard or inconvenience as long as irritation problems are absent.
  • the present invention thus relates to 1-alkyl or 1-alkylaryl esters of 11 epi PGF 2alpha to be used for treating glaucoma or ocular hypertension.
  • the alkyl chain of the 1-alkyl esters comprises 1-10, preferably 1-7, and especially 1-5 carbon atoms.
  • the 1-alkylaryl esters have an aryl group monosubstituted by a lower alkyl chain. This lower alkyl chain has 1-5 carbon atoms.
  • the 11 epi PGF 2alpha -1-isopropyl ester is used.
  • compositions for the treatment of glaucoma or ocular hypertension said compositions containing an effective intraocular pressure reducing amount of at least one 11 epi PGF 2alpha -1-ester defined as above, in an ophthalmoiogically compatible vehicle.
  • effective amount here means that the composition contains about 0.1-10 ⁇ g, especially 1-10 ⁇ g of the active substance.
  • the ophthalmologically compatible vehicle which may be employed for preparing compositions of this invention.
  • the vehicle furthermore may contain ophthalmolegically compatible preservatives such as e.g. benzalkonium chloride, surfactants like e.g. Tween® 80, liposomes or polymers, for example methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and hyaluronic acid; these may be used for the purpose of increasing the viscosity.
  • ophthalmolegically compatible preservatives such as e.g. benzalkonium chloride, surfactants like e.g. Tween® 80, liposomes or polymers, for example methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and hyaluronic acid; these may be used for the purpose of increasing the viscosity.
  • a method for treating glaucoma or ocular hypertension consists in contacting a composition as aforesaid with the eye in order to reduce eye pressure and to maintain said pressure on a reduced level.
  • the composition contains 0.1-10 ⁇ g, especially 1-10 ⁇ g, of the active substance i.e. the 11 epi PGF 2alpha ester; the treatment may advantageously be carried out in that one drop of the composition, corresponding to about 30 ⁇ l, is administered about 1 to 4 times to the patient's eye.
  • PGF 2alpha -1-isopropyl ester or 11 epi PGF 2alpha -1-isopropyl ester produced according to Example 1 was mixed with an eye drop solution containing 0.5 % Tween 80 as a micelle-forming substance plus 0.01 % benzalkonium chloride as a preservative to 50 ⁇ g/ml concentration. Healthy volunteers received in one of their eyes one drop (30 ⁇ l) containing 1.5 ⁇ g of either PGF 2alpha -1-isopropyl ester or 11 epi PGF 2alpha -1-isopropyl ester, and in the other eye one drop of the vehicle without any added prostaglandin compound, this other eye being the contralateral control eye.
  • Eye pressures were measured 2, 4, 6 and 8 hours after administration of 11 epi PGF 2alpha ,-1-isopropyl ester, and 4 and 8 hours after administration of PFG2 alpha -1-isopropyl ester. With prostaglandin eye drops the maximum pressure reducing effect in the eye is expected to be achieved 6-8 hours after administration of the preparation.
  • Eye pressure was measured by means of applanation tonometry, either with Godmann's applanation tonometer or with a pneumatonometer (Digilab Mode -30RT), after anesthesia of the cornea with oxybuprocaine drops or with a mixture of oxybuprocaine and fluorescein. Results could be read only after measurements were complete.
  • This pressure reduction may appear to be a small one, but it is a well-known fact that normotensive individuals will generally show fairly little reaction in response to pressure reducing drugs. This is true also of e.g. pilocarpine and timolol.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)

Claims (10)

1. 1-Alkyl- oder 1-Alkylarylester von 11-epi-PGF2a zur Verwendung in der Behandlung von Glaukom oder Augenüberdruck.
2. 11-epi-PGF2a-1-Alkylester zur Verwendung gemäß Anspruch 1, dadurch gekennzeichnet, daß die Alkylkette 1 bis 10, vorzugsweise 1 bis 7, und insbesondere 1 bis 5 Kohlenstofiatome besitzt.
3. 11-epi-PGF2a-1-Alkylarylester zur Verwendung gemäß Anspruch 1, dadurch gekennzeichnet, daß die Arylgruppe durch eine niedere Alkylgruppe mit 1 bis 5 Kohlenstoffatomen monosubstituiert ist.
4. 11-epi-PGF2a-1-Isopropylester zur Verwendung in der Behandlung von Glaukom oder Augenüberdruck.
5. Zusammensetzung für die lokale Behandlung von Glaukom oder Augenüberdruck dadurch gekennzeichnet, daß sie eine wirksame, den intraokularen Druck reduzierende, Menge von 11-epi-PGF2a-1-Ester, wie es in irgendeinem der Ansprüche 1 bis 4 bestimmt ist, in einem ophthalmologisch verträglichen Träger enthält.
6. Zusammensetzung gemäß Anspruch 5, dadurch gekennzeichnet, daß der ophthalmologisch verträgliche Träger eine physiologische Salzlösung, eine Öllösung oder eine Salbe ist, und daß er gegebenenfalls ophthalmologisch verträgliche Konservierungsstoffe, oberflächenaktive Stoffe, Liposome oder Polymere enthält.
7. Verwendung von 1-Alkyl- oder 1-Alkylarylester von 11-Epi-PGF2a zur Herstellung einer Zusammensetzung für die lokale Behandlung von Glaukom oder Augenüberdruck.
8. Verwendung gemäß Anspruch 7, in der der 11-Epi-PGF2a-Ester ein 1-Alkylester mit 1 bis 10, vorzugsweise 1 bis 7 Kohlenstoffatomen in der Alkylkette ist.
9. Verwendung gemäß Anspruch 8, in der der 11-Epi-PGF2a-Ester der 1-Isopropylester ist.
10. Eine Zusammensetzung, die 0,10 bis 10 µg eines Esters gemäß Anspruch 1 enthält, zur Verwendung in einem Verfahren zur Behandlung von Glaukom oder Augenüberdruck, worin das Auge mit der Zusammensetzung in Kontakt gebracht wird.
EP88908778A 1987-10-07 1988-10-06 Prostaglandin-derivate zur behandlung von glaucoma oder augenüberdruck Expired - Lifetime EP0344235B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT88908778T ATE78031T1 (de) 1987-10-07 1988-10-06 Prostaglandin-derivate zur behandlung von glaucoma oder augenueberdruck.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8703854 1987-10-07
SE8703854A SE8703854D0 (sv) 1987-10-07 1987-10-07 Prostaglandinderivat for behandling av glaukom eller okuler hypertension

Publications (2)

Publication Number Publication Date
EP0344235A1 EP0344235A1 (de) 1989-12-06
EP0344235B1 true EP0344235B1 (de) 1992-07-08

Family

ID=20369771

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88908778A Expired - Lifetime EP0344235B1 (de) 1987-10-07 1988-10-06 Prostaglandin-derivate zur behandlung von glaucoma oder augenüberdruck

Country Status (6)

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EP (1) EP0344235B1 (de)
JP (1) JP2852057B2 (de)
AT (1) ATE78031T1 (de)
DE (1) DE3872701T2 (de)
SE (1) SE8703854D0 (de)
WO (1) WO1989003384A1 (de)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2021316C (en) * 1989-07-27 2000-10-24 Ming Fai Chan Intraocular pressure reducing 11-acyl prostaglandins
US4994274A (en) * 1989-07-27 1991-02-19 Allergan, Inc. Intraocular pressure reducing 11,15-diacyl prostaglandins and method of using
US5011856A (en) * 1990-03-12 1991-04-30 Allergan, Inc. Use of prostaglandin F3 α as an ocular hypotensive agent
HUT61666A (en) * 1990-03-19 1993-03-01 Allergan Inc Process for producing pharmaceutical composition containing 5-trans-prostaglandine f2a- for reducing eye-pressure
US5238961A (en) * 1990-06-14 1993-08-24 Allergan, Inc. Pgf 1-alcohols and their use as ocular hypotensives
DE4036140A1 (de) * 1990-11-09 1992-05-14 Schering Ag 9-halogen-11ss-hydroxy-prostaglandinderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
US6124353A (en) * 1992-11-12 2000-09-26 Allergan Sales, Inc. Method of treating ocular hypertension with 8-epi prostaglandins
KR950000664A (ko) * 1993-06-14 1995-01-03 우에노 도시오 신규한 13,14-디히드로-피지에프 2 베타(PGF2β) 및 이의 이소프로필 에스테르
DE69823852T2 (de) 1997-02-04 2005-05-19 Johnstone, Murray A., Seattle Verfahren zur förderung des haarwuchses und entwicklung des haarsystems
NZ513825A (en) 1999-03-05 2001-09-28 Procter & Gamble C 16 unsaturated FP-selective prostaglandins analogs
US20020013294A1 (en) 2000-03-31 2002-01-31 Delong Mitchell Anthony Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US20020172693A1 (en) 2000-03-31 2002-11-21 Delong Michell Anthony Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9216183B2 (en) 2002-02-04 2015-12-22 Allergan, Inc. Topical treatment for chemotherapy induced eyelash loss or hypotrichosis using prostamide F2 alpha agonists
US8758733B2 (en) 2002-02-04 2014-06-24 Allergan, Inc. Topical treatment for chemotherapy induced eyelash loss or hypotrichosis using prostamide F2 alpha agonists
US7351404B2 (en) 2002-02-04 2008-04-01 Allergan, Inc. Method of enhancing hair growth
US9149484B2 (en) 2009-11-09 2015-10-06 Allergan, Inc. Compositions and methods for stimulating hair growth
NZ628266A (en) 2009-11-09 2016-02-26 Allergan Inc Compositions and methods for stimulating hair growth
US10272040B2 (en) 2010-08-12 2019-04-30 Nanyang Technological University Liposomal formulation for ocular drug delivery
US8859616B2 (en) 2011-01-21 2014-10-14 Allergan, Inc. Compounds and methods for enhancing hair growth
US9956195B2 (en) 2014-01-07 2018-05-01 Nanyang Technological University Stable liposomal formulations for ocular drug delivery

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE391714B (sv) * 1970-09-11 1977-02-28 Upjohn Co Forfarande for framstellning av prostaglandiner av typ pge?712 med foreningar av typ pga?712 som utgangsforeningar
US4599353A (en) * 1982-05-03 1986-07-08 The Trustees Of Columbia University In The City Of New York Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma

Also Published As

Publication number Publication date
DE3872701D1 (de) 1992-08-13
JP2852057B2 (ja) 1999-01-27
ATE78031T1 (de) 1992-07-15
DE3872701T2 (de) 1992-12-03
WO1989003384A1 (en) 1989-04-20
SE8703854D0 (sv) 1987-10-07
EP0344235A1 (de) 1989-12-06
JPH02501483A (ja) 1990-05-24

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